Postgrad Med J: first published as 10.1136/pgmj.56.657.491 on 1 July 1980. Downloaded from

Postgraduate Medical Journal (July 1980) 56, 491-493

Corticosteroid treatment, serum and coronary artery disease D. B. JEFFERYS M. H. LESSOF B.Sc., M.R.C.P. M.D., F.R.C.P. M. B. MATTOCK Ph.D.

Department of Medicine, Guy's Hospital, London Bridge SE] 9RT

Summary out of the tissue and back into the general Serum lipids and the cholesterol concentrations in the metabolic pool, where it may be catabolized. high density lipoprotein (HDL) fractions were meas- In this study the authors have looked at the long- ured in patients receiving long-term term effects of on HDL cholesterol. treatment for connective tissue disorders and asthma. They have studied 3 groups: patients who are receiv- Patients who were not receiving corticosteroid ing corticosteroids; age-, sex- and disease-matched treatment had levels which did not differ patients who are not receiving such treatment; and from those of healthy people. However, female (but healthy age- and sex-matched controls. not male) patients who had received prednisolone for a mean period of 3-1 years had a significant elevation Patients and methods in total cholesterol and a large decrease in HDL Subjects cholesterol. It seems possible that high levels of The serum total cholesterol, and copyright. corticosteroids may increase the incidence of pre- HDL cholesterol were measured for 16 pre-meno- menopausal ischaemic disease in females. pausal female patients (age range 18-34 years) and 15 males (ages 24-38 years) who were all receiving Introduction long-term corticosteroid treatment. The body weights Corticosteroids are frequently used in the long- were all within 5% of the predicted weight from term management of connective tissue disorders and standardized life assurance tables. Three of the occasionally in patients with asthma and sarcoid. females were taking an oral

contraceptive, whilst http://pmj.bmj.com/ In addition to the traditional complications of this only 2 of the males and none of the females were treatment, Kalbak (1972) showed an increase in cigarette smokers. None had a known family history peripheral during corticosteroid ofhyperlipidaemia. The average dose of prednisolone treatment for rheumatoid arthritis. As compared to was 17-0 mg/day for the females and 17-2 mg for the well matched controls, Bulkley and Roberts (1975) males. The mean duration of treatment was 3-1 found an increased incidence of coronary athero- years for the females and 3-4 years for the males. sclerosis at post-mortem in 36 patients who had The patients studied were all in remission from received corticosteroids for a variety of conditions their disease at the time of investigation. This was on September 24, 2021 by guest. Protected including systemic lupus and rheumatoid arthritis. judged from clinical impression and from sedi- An increased incidence of coronary artery disease mentation rates, biochemical profiles and respiratory has also come to be recognized in renal transplant function tests. patients on corticosteroids (Evans and Ghosh, Three of the patients with Behret's syndrome 1979). were taking azathioprine 50 mg twice/day, one of the The mechanism for this accelerated atherosclerosis rheumatoids was taking naproxen 200 mg thrice/day is unclear. El-Shaboury and Hayes (1973) showed and one patient with urticarial vasculitis was receiving that both triglycerides and cholesterol were increased cimetidine 400 mg at night. Apart from the asthma- in 100 female asthmatics on long-term corticosteroid tics, who were using bronchodilator aerosols, the treatment. Current interest in lipid patients were on no other regular medica- centres on the high density lipoproteins and their tions. In the control group 3 patients were taking inverse relationship to ischaemic heart disease azathioprine 100 mg daily. (Gordon et al., 1977). These levels may be parti- The conditions for which they were receiving cularly significant if, as has been suggested, high prednisolone were mainly connective tissue disorders, density lipoproteins are responsible for transferring including Behget's syndrome (13), systemic lupus 0032-5473/80/0700-0491 $02.00 © 1980 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.56.657.491 on 1 July 1980. Downloaded from

492 D. B. Jefferys, M. H. Lessof and M. B. Mattock

(2), rheumatoid arthritis (4), polyarteritis (2), to HDL ratio is one of the most sensitive predictors urticarial vasculitis (2), sarcoidosis (4) and asthma of coronary artery disease (Miller et al., 1977). (4). The blood samples were taken after a 14-hr In such studies, pre-menopausal women have higher fast. HDL cholesterol concentrations. From the authors' observation, long-term corticosteroid treatment Methods appears to reverse the usual pre-menopausal The fasting serum and cholesterol pattern of HDL cholesterol. Indeed, by generally concentrations and the cholesterol concentrations accepted criteria young female patients in this study of the high density lipoprotein (HDL) fractions were were likely to have a considerably increased risk assayed by standard Technicon Autoanalyser II of premature coronary artery disease. In keeping enzymatic methods. with this, 2 of the female patients have a history of The HDL fraction was measured in the super- angina pectoris with exercise ECG changes. They natant following specific precipitation from serum had no family history of ischaemic heart disease. of very low density and low density lipoproteins It was felt important to exclude a primary effect by sodium phosphotungstate and magnesium of the disease on the serum lipid concentrations, or chloride (Lopes Virella, Stone and Colwell, 1977). the influence of other drugs on lipid metabolism. It has been confirmed that this method shows good The patients studied were all young and were in agreement with a reference ultracentrifugal technique remission from their various diseases at the time of of HDL separation (Mattock et al., 1979). investigation. Many had been referred for an opinion as to whether their corticosteroids could be Results reduced or steroid-sparing drugs introduced. The There was no significant difference between the study was designed to compare the patients on disease-, age- and sex-matched controls, compared with disease-matched controls and healthy to the healthy controls, in any of the serum lipids subjects. This was facilitated by the fact that the (Table 1). A notable difference was found between authors were simultaneously looking at a large the male and female patients receiving cortico- group of patients with Behcet's syndrome (Lessof steroids. The male patients had lower levels of et al., 1979). It could be argued that either thecopyright. triglycerides and total cholesterol. They had connective tissue disease, or additional drug therapy, significantly higher levels of HDL cholesterol and such as immunosuppressives, would alter the blood of the total cholesterol to HDL cholesterol ratio lipids. In fact only 3 patients were receiving, or had (P<0001). Thus long-term corticosteroids appear received, azathioprine in addition to the cortico- to reverse the usual higher HDL levels seen in steroids. Three similar patients on azathioprine females. were therefore included in the disease-matched control group. Since the patients were in remission Discussion it was possible to establish well matched controls. http://pmj.bmj.com/ The principal finding of this study was the Several of the patients were on inappropriately high marked sex difference in the effect of long-term doses of steroids and these were subsequently corticosteroid administration on HDL cholesterol. reduced without ill effect. Epidemiological studies of ischaemic heart disease Attention was also paid to the other factors which have shown that there is an inverse relationship are known to influence HDL concentrations. with HDL cholesterol and that the cholesterol Obesity, cigarette smoking and alcohol consumption on September 24, 2021 by guest. Protected

TABLE 1. Results Serum lipids and high density lipoprotein (HDL) cholesterol all in mmol/l (+s.d.) Corticosteroid Disease-matched Healthy Significance, controls Group group controls controls v. steroid group Total triglycerides Male (n= 15) 1-21 (0-42) 0 90 (0-21) 0-87 (0 56) NS (mmol/l) Female (n= 16) 1-84 (0 55) 0 91 (0 29) 0 90 (0-28) P<0-05 Total cholesterol Male 5-61 (0 28) 5 33 (0-31) 5 28 (0 15) NS (mmol/1) Female 6 58 (1-04) 4-81 (0-81) 4-93 (0-57) P<0-05 HDL cholesterol Male 1-40 (0-31) 1-54 (0 15) 1 50 (0-53) NS (mmol/l) Female 1-10 (0-26) 1 99 (0-25) 1-78 (0 35) P<0-01 Ratio of Total cholesterol Male 4 00 3-46 3-71 NS HDL cholesterol Female 5 98 2-42 2-78 P<0-001 Postgrad Med J: first published as 10.1136/pgmj.56.657.491 on 1 July 1980. Downloaded from

Corticosteroid treatment and coronary heart disease 493 were found to be similar within the groups. No disease in itself and, particularly in female patients, glucose intolerance was noted. Three of the female should be kept to a minimum. patients were taking oral contraceptives but their HDL cholesterol levels were in the range seen in other female patients. It was therefore concluded that the sex difference in HDL concentration was References BULKLEY, B.H. & ROBERTS, W.C. (1975) The heart in systemic attributable to the corticosteroid treatment rather lupus erythematosus and the changes induced in it by than to the disease or to other therapy. corticosteroid therapy. American Journal of Medicine, 58, The accelerated atherosclerosis seen in patients on 243. corticosteroids has been above. EL-SHABOURY, A.H. & HAYES, T.M. (1973) Hyperlipidaemia long-term quoted in asthmatic patients receiving long-term steroid therapy. El-Shaboury and Hayes (1973) found a significant British Medical Journal, 2, 85. increase in serum triglycerides amongst 100 female EVANS, D.B. & GHOSH, P. (1979) Plasma lipoproteins in asthmatics receiving this treatment, and it is of renal transplant patients. British Medical Journal, 1, 21. interest that and Roberts' GORDON, T., CASTELLI, W., HJORTLAND, M.C., KANNEL, W. Bulkley (1975) patients & DAWBER, T. (1977) High density lipoprotein as a pro- with systemic lupus and coronary artery disease- tective factor against coronary heart disease. American like lupus patients in general-were predominantly Journal of Medicine, 62, 707. female. GOTTO, A.M., MILLER, N.E. & OLIVER, M.F. (Eds) (1978) Savdie et al. have a rise in HDL High Density Lipoproteins and Atherosclerosis. Excerpta (1979) reported Medica, Amsterdam. cholesterol after successful renal transplantation JEFFERYS, D.B. & WHITE, I.R. (1973) The lipid response to but have provided no explanation for this. In view of female gonadal in rats. Nutrition Reports the authors' own findings and the other evidence International, 8 (3), 201. it seems that the reduction in KALBAK, K. (1972) The incidence of arteriosclerosis in quoted here, likely patients with rheumatoid arthritis receiving long-term prednisolone dose after successful transplantation corticosteroid therapy. Annals of the Rheumatic Diseases, may well have been a factor. 31, 196. Young women usually have higher HDL chol- LESSOF, M.H., JEFFERYS, D.B., LEHNER, T. .MATTOCK, M. & esterol levels than do men and have a low incidence SAUNDERS, M.D. (1979) Corticosteroids and azathioprine: their use in Behcet's syndrome. Chapt. 22. In: Behcet's copyright. of ischaemic heart disease. The protective effect of Syndrome (Ed. by Lehner, T. & Barnes, C.G.). Academic female sex hormones is not simple, however, since Press, London. the contraceptive pill has an opposite effect (Ory, LOPES-VIRELLA, M., STONE, P. & COLWELL, J. (1977) Serum and so does exogenous sex adminis- high density lipoprotein in diabetic patients. Diabetologia, 1977) 13, 285. tration in animals (Jefferys and White, 1973). MATTOCK, M.B., FULLER, J.H., PAMELA, S.M. & KEEN, H. However the effect of prednisolone on endogenous (1980) Lipoproteins and plasma cholesterol esterification sex hormones is unknown. in normal and diabetic subjects. Atherosclerosis (in press). The female cortico- MILLER, N.E., FORDE, O.H., THELLE, D.S. & MOJOS, O.D. patients receiving long-term http://pmj.bmj.com/ steroid treatment to have the increased risk (1977) High density lipoprotein and coronary heart disease; appear a prospective case-control study. Lancet, i, 965. of developing coronary artery disease, which the ORY, H.W. (1977) Association between oral contraceptives male patients do not have. The mechanism for this and myocardial infarction. Journal of the American protection is not clear but may involve changes in Medical Association, 237, 2619. sex and SAVDIE, E., GIBSON, J.C., STEWART, J.H. & SIMONS, L.A. endogenous hormone production transport. (1979) High density lipoproteins in chronic renal failure Whatever the short-term benefits, the present results and after renal transplantation. British Medical Journal, also emphasize that corticosteroid treatment is a 1, 928. on September 24, 2021 by guest. Protected